Recent advances in understanding depressive disorder: Possible relevance to brain stimulation therapies.

Recent research has provided novel insights into the major depressive disorder (MDD) and identified certain biomarkers of this disease. There are four main mechanisms playing a key role in the related pathophysiology, namely (1) monoamine systems dysfunction, (2) stress response, (3) neuroinflammation, and (4) neurotrophic factors alteration. Robust evidence on the decreased homovanillic acid in the cerebrospinal fluid (CSF) of patients with MDD supports a rationale for therapeutic stimulation of the medial forebrain bundle activating the dopamine reward system. Both activation and suppression of the hypothalamic-pituitary-adrenal (HPA) axis in MDD and related conditions indicate usefulness of its evaluation for the disease subtyping. Elevated proinflammatory cytokines (specifically, interleukin-6) in CSF imply the role of neuroinflammation resulting in activation of the tryptophan-kynurenine pathway. Finally, neuroplasticity and trophic effects of the brain-derived neurotrophic factor (BDNF) may be related to both structural abnormalities of the brain in MDD and the underlying mechanisms of various therapies. In addition, the gut-brain interaction is pivotal, since lack of beneficial microbes confer the risk of MDD through negative effects on the dopamine system, HPA axis, and vagal nerve. All these factors may be highly relevant to treatment of MDD with contemporary brain stimulation therapies.